Placental development is a complex process that involves interactions among multiple cell types and may be affected by maternal nutrition during pregnancy. Further, the fetal origin of adult disease hypothesis posits that maternal nutrition during pregnancy has consequences for the future adult health of the fetus. The hypothesis underlying this proposal is that the hormone leptin influences multiple steps in the process of placental development. Leptin is produced by fat cells, and thus is a potential mediator of the effects of nutrition on placental development. In the mentored phase of this proposal, the first specific aim is to determine the role of leptin in trophoblast cell specification during preimplantation development. These experiments will localize leptin in the early embryo and determine whether the distribution of leptin is required for trophoblast cells to form. The second aim is to determine the mechanism of leptin-induced trophoblast invasiveness. These experiments will explore the cell signaling pathways and changes in gene expression that underlie leptin stimulation of trophoblast invasion. In the independent phase of this proposal, the first specific aim is to determine whether leptin mediates effects of nutrition on fetal and placental programming. Animals will be placed on a restricted diet with or without leptin treatment, and the effects on placental development and adult adiposity determined. The second specific aim is to determine effects of leptin on placental cell type differentiation. Trophoblast stem cells will be used to study the role of;leptin in the differentiation of giant cell, syncytiotrophoblast cell, and spongiotrophoblast cell types. My goal is to establish an independent laboratory in reproductive biology to pursue research on the effects of maternal environment on placental development. This grant would provide an opportunity for training in specific techniques and broader scientific questions in a leading laboratory in placental biology, and would allow me to pursue an independent line of research in this laboratory. The proposed project is relevant to human health in at least two ways. First, insufficient trophoblast invasion is associated with pre-eclampsia, the most common complication of pregnancy, and one which can be fatal. This project will examine one of the influences on trophoblast invasion. Second, this project will increase our understanding of the ways in which maternal nutrition during pregnancy, may influence placental development, and even adult health.;